5-keto-2, 4, 6, 8-tetrahydroimidazolo [4, 5-c] thiophenes and process for preparing the same



Patented Apr. 15, 1947 5 KETO 2,4,6,8 TETRAHYDROIMIDAZOLO [4,5-C]THIOPHENES AND PROCESS FOR PREPARING THE SAME Seymour Bernstein, PearlRiver, Bernard R. Baker, Nanuet, and Sidney R. Safir, Pearl River, N.Y., assignors by mesne assignments,

to American Cyanamid Company, New York,

N. Y., a corporation of Maine No Drawing. Application February 14, 1945,Serial No. 577,943

9 Claims.

This invention relates to new organic compounds and to methods of theirpreparation. More particularly, the invention relates to the preparationof 5-keto-2,4,6,8-tetrahydroimidaz- Our invention will now beillustrated in greater particularity by means of the following specificexamples. Different reaction conditions and intermediates may beemployed without departolo-[4,5-c] thiophenes and reaction products 5ing from the scope of the invention as defined thereof. by the appendedclaims.

We have found that when an acid addition salt Exam le 1 of a3-amino-4-keto-thiophane is mixed with p cyanic acid, or a salt ofcyanic acid, in an ap- To a Stirred mixture f 8- of hippuric ac d.propriate solvent, at -keto-2,4,6,8-tetrahydro- 10 .6 g. of anhydroussodium acetate and 11.6 g. of imidazolo-'[4,5-c] thiophene is obtained.This acetic anhyd i e Was added. during fifteen reaction may beillustrated by the following minutes, 30 g. of ethyl rmylvalerate. Thereequation; suiting mixture was heated at 60 C. for three 0 hours withstirring, then poured into iced water. U The oil which separated wasextracted with ether, f the ether solution was dried and evaporated. The-CNH.HM HN NH XM residue, an orange-red oil, contained the azlac- J itone of 2 benzoylamino 7 carbethoxy-Z-hep- I I H tenoic acid. 3 R+XCNO QA solution of 6.6 g. of the azlactone of 2- wherein R is an alkylradical, an w-carboxyalkyl radical or an w-carbalkoxyalkyl radical, M isthe anion of an acid, and X is hydrogen, alkali metal or an ammoniumradical.

As will be apparent from the above equation, acid addition salts of3-amino-4-ketothiophanes are used as intermediates. These are newcompounds but may be prepared by the series of reactions shown in thespecific examples.

benzoylamino-'7-carbethoxy-2-heptenoic acid and 2.6 cc;ethylthioglycolate in 33 cc. of dry ethanol was treated with 0.1 cc. ofpiperidine and refluxed one-half hour. Then an additional 0.1 cc. ofpiperidine was added and the solution was refluxed one-half hour longer.Upon evaporation to dryness, 7.5 g. of an oil was obtained. A mixture ofthe oil, 80 cc. dry ethanol, 2.6 cc. ethylthioglycolate and 0.2 cc.piperidine was refluxed two and one-half hours, then evaporated todryness. The yield of ethyl a-benzoyl-aminop-(carbethoxymethylthio)suberate was 7.3 g., obtained as an .oil.

To the dry sodium ethoxide from 1.3 g. of sodium obtained by evaporatingthe alcoholic solution to dryness, was added in a nitrogen atmosphere2.8 cc. of ethylthioglycolate in 25 cc. of benzene, followed by 7.3 g.of crude ethyl 6- benzoyl amino B (carbethoxymethylthio) suberate in 35cc. benzene. The mixture was protected from moisture and refluxed fortwo and one-half hours. It was then cooled, diluted with ether, washedtwice with iced water and with 3% sodium hydroxide. The combined aqueouswash- The reaction can take place at temperatures of 5 ings wereacidified with acetic acid, the mixture from about 0 C. to about 40 C.,which obviously was extracted with ether, the ether layer was will varythe reaction time from that given above. washed in succession withwater, sodium bicar- The compounds of the present invention are bonateand water, and finally evaporated to dryuseful principally asintermediates in the prepness in vacuo. The product,2-6-carbethoxybutylaration of other useful organic compounds and3-benzoylamino-4-keto-5-carbethoxy-thiophane,

pharmaceuticals, such as biotin.

was obtained as an oil.

A mixture of 3.1 g. of the compound obtained immediately above, 20 cc.acetic acid and 20 cc. of 6 N hydrochloric acid was refluxed for fiveand one-half hours. A total of 20 cc. 12 N hydrochloric acid was addedin five portions during the first three hours. The mixture was cooled toC. and filtered. The filtrate was diluted with an equal volume of waterand extracted thoroughly with ether. The aqueous layer was evaporated todryness. The crystalline residue was dissolved in 30 cc. water, treatedwith Norit and filtered. The filtrate was evaporated to dryness. Thecolorless, crystalline residue consisted of 1.1 g. of2-5-carboxybutyl-3-amino 4 ketothiophane hydrochloride.

To a solution of 1.1 g. of the above hydrochloride in cc. water wasadded a solution of 0.70 g. potassium cyanate in 5 cc. water. A nearlycolorless crystalline substance separated. This was filtered, washed anddried. A yield of 0.70 g. of 2-6-carboxybutyl-5-keto-2,4,6,8-tetrahydroimidazolo-[4,5-cl thiophene was obtained.

In the above example, R of the general equation is a carboxybutylradical. R can be other carboxyalkyl radicals, such as carboxymethyl,carboxyethyl, carboxypropyl, carboxyisopropyl, carboxyamyl,carboxyhexyl, etc. When an acid addition salt of3-amino-4-ketothiophane, in which R is a carbalkoxyalkyl radical, isused as an intermediate, we can prepare 5-keto-2,4,6,8-tetrahydroimidazolo-[4.5-0] thiophenes in which R will be acarbethoxybutyl, carbethoxypropyl, carbethoxyethyl, carbethoxymethyl,carbomethoxybutyl, carbomethoxypropyl, carbomethoxyethyl,carbomethoxymethyl, carbomethoxyamyl, or similar radical.

In the above example, the intermediate used was the hydrochloride of a3-amino-4-ketothiophane. We can use other acid addition salts in placeof the hydrochloride, such as the sulfate, phosphate, nitrate,hydrobromide, and the like.

Example 2 0.16 g. sodium and 10 cc. dry ethanol was added,

under a nitrogen atmosphere, cc. benzene, followed by a solution of 1.26g. of the ester prepared above in 25 cc. benzene. The mixture wasrefluxed two hours, cooled to 0 C., diluted with a little ether andextracted several times with iced water. The aqueous washings were addedimmediately to excess, cold dilute acetic acid. Sodium chloride wasadded and the oil was extracted with ether. The ether solution waswashed with water, dried with magnesium sulfate. and evaporated. Theyield of 2-methyl 3 benzoylamino-4-keto-5- carbethoxythiophane was 0.85g., obtained as an orange-yellow gum.

A mixture of 1.0 g. of the compound prepared immediately above and 11cc. 6 N hydrochloric acid was heated on a steam-bath for fifteen andone-half hours. Water was added to the mixture and the gummy materialwas removed by washing several times with ether. The aqueous layer wastreated with Norit, and the filtrate was evaporated 4 4 to dryness. Theresidue was dissolved in dry ethanol, the solution was treated withNorit, flltered, and the filtrate was evaporated to dryness. The residueconsisted of 0.25 g. of 2-methyl-3- amino-4-ketothiophane hydrochloride.

A solution of 200 mg. of the amino ketothiophane above in 3 cc. waterwas treated with 200 mg. potassium cyanate. A clear solution resulted atfirst, followed by separation of colorless crystals. The latter werefiltered and washed with 1 cc. water. The yield of 2-methyl-5-keto-2,4,6,8-tetrahydro imidazolo [4,5-c] thiophene was mg.

In the above example, R of the general equation is methyl. We can use asintermediates other acid addition salts of 3-amino-4-ketothiophane inwhich R is an alkyl radical such as ethyl, propyl, isopropyl, butyl,isobutyl, amyl, isoamyl. and the like.

We claim: 1. Compounds having the formula:

0 II HN IIIH wherein R is a member of the group consisting of alkylradicals, carboxyalkyl radicals and carbalkoxyalkyl radicals.

2. 2 carboxybutyl 5 keto 2,4,6,8 tetra hydroimidazolo-[4,5-c] thiophene.

3. 2 methyl 5 keto 2,4,6,8 tetrahydro imidazolo-[4,5-c] thiophene.

4. 2 carbomethoxy 5 keto 24.6.8 tetra hydroimidazolo-[4,5-cl thiophene.

5. A method preparing 5-keto-2,4,6,8tetrahydroimldazolo- [4,5-clthiophenes having the formula:

wherein R is a member of the group consisting of alkyl radicals,carboxyalkyl radicals and carbalkoxyalkyl radi:als, which comprisesmixing an acid addition salt of a compound having the formula:

wherein R is as above with a member of the group consisting of cyanicacid and salts of cyanic acid.

6. A method of preparing 5-keto-2,4,6,8-tetrahydroimidazolo- [4,5-0]thiophenes having the formula:

wherein R is a member of the group consisting of alkyl radicals,carboxyalkyl radicals, and carbalc imes koxyaliwi radicals, whihcomprises mixing a compound having the formula:

wherein R is as above, with potassium cyanate.

7. A method of preparing 2-carboxybutyl-5- keto 2.4,8,8tertahydroimidazoio [4,5 c] thiophene which comprises mixingz-carboxybuty1-3-amino-d-ketothiophane hydrochloride with potassiumcyanate.

8. A method of preparing 2-methyl-5-keto- 2,4,6.8-tetrahydroimidazo1o-[4,5 c] thiophene lq ride with potassium cyanate.

